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1.
Cancer Res ; 83(19): 3174-3175, 2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37779426

RESUMEN

The ongoing therapeutic revolution in multiple myeloma care can be traced to the turn of the millennium with the unanticipated discovery in 1999 that the cereblon binding small molecule thalidomide had profound clinical effectiveness and, simultaneously, the emergence of a new class of targeted therapies inhibiting the proteasome, both of which ultimately target ubiquitinated protein degradation. These contemporaneous discoveries forever changed the landscape of multiple myeloma care, substantially extending survival. Foreshadowing this seismic change, Nobel Prize winning work on the proteasome ubiquitin pathway had stimulated the development of highly specific proteasome inhibitor small molecules, particularly PS-341 (later named bortezomib). An abundance of the proteasome in hematologic malignancies had been recognized and thus PS-341 was logically being explored in relevant preclinical models. Concurrent with phase I trials, which were soon to prove the significant clinical relevance of preclinical models, the laboratory of Dr. Kenneth Anderson and colleagues at Dana-Farber, in partnership with Dr. Julian Adams and scientists at ProScript (later Millennium Pharmaceuticals) first demonstrated that the proteasome inhibitor PS-341 inhibited growth, induced apoptosis, and overcame drug resistance in human multiple myeloma cells. This landmark paper in Cancer Research set the stage for a paradigm shift in how multiple myeloma was managed across all stages of the disease, which changed the lives of patients worldwide. See related article by Hideshima and colleagues, Cancer Res 2001;61:3071-6.


Asunto(s)
Antineoplásicos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Bortezomib , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Complejo de la Endopetidasa Proteasomal , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Pirazinas/farmacología
2.
Elife ; 122023 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-37753907

RESUMEN

Drug resistance is a challenge in anticancer therapy. In many cases, cancers can be resistant to the drug prior to exposure, that is, possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance in cancer cell lines or characterize intrinsic drug resistance without a priori knowledge of its cause. We hypothesized that cell morphology could provide an unbiased readout of drug resistance. To test this hypothesis, we used HCT116 cells, a mismatch repair-deficient cancer cell line, to isolate clones that were resistant or sensitive to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then expanded these clones and measured high-dimensional single-cell morphology profiles using Cell Painting, a high-content microscopy assay. Our imaging- and computation-based profiling pipeline identified morphological features that differed between resistant and sensitive cells. We used these features to generate a morphological signature of bortezomib resistance. We then employed this morphological signature to analyze a set of HCT116 clones (five resistant and five sensitive) that had not been included in the signature training dataset, and correctly predicted sensitivity to bortezomib in seven cases, in the absence of drug treatment. This signature predicted bortezomib resistance better than resistance to other drugs targeting the ubiquitin-proteasome system, indicating specificity for mechanisms of resistance to bortezomib. Our results establish a proof-of-concept framework for the unbiased analysis of drug resistance using high-content microscopy of cancer cells, in the absence of drug treatment.


Asunto(s)
Antineoplásicos , Microscopía , Bortezomib/farmacología , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Pirazinas/farmacología , Resistencia a Antineoplásicos , Línea Celular Tumoral , Antineoplásicos/farmacología , Inhibidores de Proteasoma/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Apoptosis
3.
Am J Transplant ; 23(6): 759-775, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36871629

RESUMEN

To date, plasma cell (PC)-targeted therapies have been limited by suboptimal PC depletion and antibody rebound. We hypothesized this is partly because of PC residence in protective bone marrow (BM) microenvironments. The purpose of this proof-of-concept study was to examine the effects of the CXCR4 antagonist, plerixafor, on PC BM residence; its safety profile (alone and in combination with a proteasome inhibitor, bortezomib); and the transcriptional effect on BMPCs in HLA-sensitized kidney transplant candidates. Participants were enrolled into 3 groups: group A (n = 4), plerixafor monotherapy; and groups B (n = 4) and C (n = 4), plerixafor and bortezomib combinations. CD34+ stem cell and PC levels increased in the blood after plerixafor treatment. PC recovery from BM aspirates varied depending on the dose of plerixafor and bortezomib. Single-cell RNA sequencing on BMPCs from 3 group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a posttreatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens.


Asunto(s)
Compuestos Heterocíclicos , Trasplante de Riñón , Humanos , Animales , Ratones , Bortezomib/farmacología , Bortezomib/uso terapéutico , Células Plasmáticas , Médula Ósea , Complejo de la Endopetidasa Proteasomal , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Movilización de Célula Madre Hematopoyética , Proyectos Piloto , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Receptores CXCR4
4.
Adv Sci (Weinh) ; 10(8): e2204866, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36683178

RESUMEN

Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid-functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, BN coordination, and π-π stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro-apoptotic reactions by promoting the dissociation of the pro-apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor-loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H2 O2 -triggered drug release, and significant cytotoxicity toward MOLM-13-Luc and MV-411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL-1 , respectively. In mice bearing MOLM-13-Luc or MV-411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid-functionalized smart nanodrugs hold remarkable potential for AML treatment.


Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Ratones , Animales , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico
5.
Expert Opin Drug Discov ; 17(12): 1329-1340, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36448326

RESUMEN

INTRODUCTION: Boron has attracted extensive interest due to several FDA-approved boron-containing drugs and other pharmacological agents in clinical trials. As a semimetal, it has peculiar biochemical characteristics which could be utilized in designing novel drugs against drug-resistant viruses. Emerging and reemerging viral pandemics are major threats to human health. Accordingly, we aim to comprehensively review the current status of antiviral boron-containing compounds. AREAS COVERED: This review focuses on the utilization of boron to design molecules against viruses from two perspectives: (i) single boron atom-containing compounds acting on miscellaneous viral targets and (ii) boron clusters. The peculiar properties of antiviral boron-containing compounds and their diverse binding modes with viral targets are described in detail in this review. EXPERT OPINION: Compounds bearing boronic acid can interact with viral targets by forming covalent or robust hydrogen bonds. This feature is valuable for combating resistant viruses. Furthermore, boron clusters can form dihydrogen bonds and bear features such as three-dimensional aromaticity, hydrophobicity, and biological stability. All these features demonstrated boron as a probable essential element with immense potential for drug design.


Asunto(s)
Antivirales , Boro , Humanos , Boro/farmacología , Boro/química , Antivirales/farmacología , Compuestos de Boro/farmacología , Compuestos de Boro/química , Compuestos de Boro/uso terapéutico , Ácidos Borónicos/química , Ácidos Borónicos/uso terapéutico , Diseño de Fármacos
6.
Mol Cancer Res ; 20(9): 1456-1466, 2022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-35604822

RESUMEN

The NF-κB signaling pathway plays key roles in inflammation and the pathogenesis of many solid and hematologic malignancies, including multiple myeloma, a malignancy of the plasma cells. While proteasome inhibitors, such as bortezomib, employed in multiple myeloma treatments may inhibit NF-κB signaling pathways, multiple myeloma cells often become drug resistant in part due to non-cell autonomous mechanism(s) from the multiple myeloma tumor microenvironment. We previously found that fragments of, but not full-length, hyaluronan and proteoglycan link protein 1 (HAPLN1), produced by multiple myeloma bone marrow stromal cells (BMSC), activate an atypical bortezomib-resistant NF-κB pathway in multiple myeloma cells. In our current study, we found that multiple myeloma cells promote HAPLN1 expression and matrix metalloproteinase 2 (MMP2) activity in cocultured BMSCs and MMP2 activity is higher in BMSCs established from multiple myeloma patients' BM aspirates relative to normal equivalents. Moreover, MMP2 cleaves HAPLN1 into forms similar in size to those previously observed in patients with multiple myeloma with progressive disease. Both HAPLN1 and MMP2 in BMSCs were required to enhance NF-κB activation and resistance to bortezomib-induced cell death in cocultured multiple myeloma cells. We propose that MMP2-processing of HAPLN1 produces a matrikine that induces NF-κB activation and promotes bortezomib resistance in multiple myeloma cells. IMPLICATIONS: HAPLN1 and MMP2 produced by BMSCs obtained from patients with multiple myeloma promote NF-κB activity and resistance to bortezomib toxicity in multiple myeloma cells, uncovering their potential as biomarkers or therapeutic targets to address bortezomib resistance in patients with multiple myeloma.


Asunto(s)
Mieloma Múltiple , Apoptosis , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Bortezomib/farmacología , Bortezomib/uso terapéutico , Línea Celular Tumoral , Resistencia a Medicamentos , Resistencia a Antineoplásicos , Proteínas de la Matriz Extracelular , Humanos , Ácido Hialurónico/uso terapéutico , Metaloproteinasa 2 de la Matriz/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , FN-kappa B/metabolismo , Proteoglicanos/uso terapéutico , Pirazinas/farmacología , Transducción de Señal , Microambiente Tumoral
7.
Curr Cancer Drug Targets ; 22(9): 741-748, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35578889

RESUMEN

Approval of the first boronic acid group-containing drug, bortezomib, in 2003 for the treatment of multiple myeloma sparked an increased interest of medicinal chemists in boronic acidbased therapeutics. As a result, another boronic acid moiety-harboring medication, ixazomib, was approved in 2015 as a second-generation proteasome inhibitor for multiple myeloma; and dutogliptin is under clinical investigation in combination therapy against myocardial infarction. Moreover, a large number of novel agents with boronic acid elements in their structure are currently in intensive preclinical studies, allowing us to suppose that at least some of them will enter clinical trials in the near future. On the other hand, only some years after bortezomib approval, direct interactions between its boronic acid group and catechol moiety of green tea catechins as well as some other common dietary flavonoids like quercetin and myricetin were discovered, leading to the formation of stable cyclic boronate esters and abolishing the anticancer activities. Although highly relevant, to date, no reports on possible co-effects of catechol group-containing flavonoids with new-generation boronic acidbased drugs can be found. However, this issue cannot be ignored, especially considering the abundance of catechol moiety-harboring flavonoids in both plant-derived food items as well as over-thecounter dietary supplements and herbal products. Therefore, in parallel with the intensified development of boronic acid-based drugs, their possible interactions with catechol groups of plant-derived flavonoids must also be clarified to provide dietary recommendations to patients for maximizing therapeutic benefits. If concurrently consumed flavonoids can indeed antagonize drug efficacy, it may pose a real risk to clinical outcomes.


Asunto(s)
Antineoplásicos , Mieloma Múltiple , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Ácidos Borónicos/uso terapéutico , Bortezomib/farmacología , Bortezomib/uso terapéutico , Catecoles/uso terapéutico , Flavonoides/farmacología , Flavonoides/uso terapéutico , Humanos , Mieloma Múltiple/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico
8.
Drug Chem Toxicol ; 45(2): 947-954, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32693643

RESUMEN

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that damages dopaminergic neurons. Zebrafish has been shown to be a suitable model organism to investigate the molecular pathways in the pathogenesis of Parkinson's disease and also for potential therapeutic agent research. Boron has been shown to play an important role in the neural activity of the brain. Boronic acids are used in combinatorial approaches in drug design and discovery. The effect of 3-pyridinylboronic acid which is an important sub-class of heterocyclic boronic acids has not been evaluated in case of MPTP exposure in zebrafish embryos. Accordingly, this study was designed to investigate the effects of 3-pyridinylboronic acid on MPTP exposed zebrafish embryos focusing on the molecular pathways related to neurodegeneration and apoptosis by RT-PCR. Zebrafish embryos were exposed to MPTP (800 µM); MPTP + Low Dose 3-Pyridinylboronic acid (50 µM) (MPTP + LB) and MPTP + High Dose 3-Pyridinylboronic acid (100 µM) (MPTP + HB) in well plates for 72 hours post fertilization. Results of our study showed that MPTP induced a P53 dependent and Bax mediated apoptosis in zebrafish embryos and 3-pyridinylboronic acid restored the locomotor activity and gene expressions related to mitochondrial dysfunction and oxidative stress due to the deleterious effects of MPTP, in a dose-dependent manner.


Asunto(s)
Intoxicación por MPTP , Pez Cebra , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Ácidos Borónicos/metabolismo , Ácidos Borónicos/uso terapéutico , Modelos Animales de Enfermedad , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología , Ratones , Ratones Endogámicos C57BL , Piridinas , Pirrolidinas/metabolismo , Pirrolidinas/uso terapéutico , Pez Cebra/metabolismo
9.
Eur J Health Econ ; 23(3): 537-549, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34546484

RESUMEN

OBJECTIVE: The study objective of this analysis was to determine the cost-effectiveness of vaborem (meropenem-vaborbactam) compared to the best available therapy (BAT) in adult patients with carbapenem-resistant Enterobacteriaceae-Klebsiella pneumoniae carbapenemase (CRE-KPC) infections from the perspective of the UK National Health Service (NHS) and Personal Social Services (PSS). METHODS: A decision tree model was developed to conduct a cost-effectiveness analysis for Vaborem compared to BAT in CRE-KPC patients over a 5 year time horizon. The model structure for Vaborem simulated the clinical pathway of patients with a confirmed CRE-KPC infection. Model inputs for clinical effectiveness were sourced from the TANGO II trial, and published literature. Costs, resource use and utility values associated with CRE-KPC infections in the UK were sourced from the British National Formulary, NHS reference costs and published sources. RESULTS: Over a 5 year time horizon, Vaborem use increased total costs by £5165 and increased quality-adjusted life years (QALYs) by 0.366, resulting in an incremental cost-effectiveness ratio (ICER) of £14,113 per QALY gained. The ICER was most sensitive to the probability of discharge to long-term care (LTC), the annual cost of LTC and the utility of discharge to home. At thresholds of £20,000/QALY and £30,000/QALY, the probability of Vaborem being cost-effective compared to BAT was 79.85% and 94.93%, respectively. CONCLUSION: Due to a limited cost impact and increase in patient quality of life, vaborem can be considered as a cost-effective treatment option compared to BAT for adult patients with CRE-KPC infections in the UK.


Asunto(s)
Enterobacteriaceae Resistentes a los Carbapenémicos , Adulto , Antibacterianos/uso terapéutico , Proteínas Bacterianas , Ácidos Borónicos/uso terapéutico , Análisis Costo-Beneficio , Combinación de Medicamentos , Enterobacteriaceae , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Humanos , Klebsiella pneumoniae , Meropenem/uso terapéutico , Calidad de Vida , Medicina Estatal , Reino Unido , beta-Lactamasas
10.
Chem Commun (Camb) ; 57(100): 13768-13771, 2021 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-34859797

RESUMEN

A novel theranostic probe called CX-B-DF is constructed for precise chemotherapy guided by near-infrared (NIR) fluorescence imaging. Moreover, the theranostic probe shows high cytotoxicity to cancer cells under dual activation (H2O2 and TP), which causes the accuracy of drug release to be improved and the toxic side effects to be reduced.


Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Cumarinas/uso terapéutico , Floxuridina/uso terapéutico , Colorantes Fluorescentes/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/metabolismo , Ácidos Borónicos/metabolismo , Línea Celular Tumoral , Cumarinas/metabolismo , Floxuridina/metabolismo , Colorantes Fluorescentes/metabolismo , Células HEK293 , Humanos , Peróxido de Hidrógeno/metabolismo , Masculino , Ratones Endogámicos BALB C , Neoplasias/diagnóstico por imagen , Imagen Óptica , Medicina de Precisión , Timidina Fosforilasa/metabolismo
11.
Chem Commun (Camb) ; 57(100): 13629-13640, 2021 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-34846393

RESUMEN

Boron was misconstrued as a toxic element for animals, which retarded the growth of boron-containing drug discovery in the last century. Nevertheless, modern applications of boronic acid derivatives are attractive in biomedical applications after the declaration that boron is a 'probable essential element' for humans by the WHO. Additionally, the approval of five boronic acid-containing drugs by the FDA has vastly impacted the use of boron in medicinal chemistry, chemical biology, drug delivery, biomaterial exploration, pharmacological improvements, and nutrition. This review article focuses on the chemistries attributed to boronic acids at physiological pH, enticing chemists to multidisciplinary applications. Prospective uses of boronic acid in pharma and chemical biology, along with prospects and challenges, are also part of the deliberation. Understanding these fundamental chemistries and interactions of boronic acid in biological systems will enable solving future challenges in drug discovery and executing space-age applications.


Asunto(s)
Ácidos Borónicos/química , Animales , Materiales Biocompatibles/química , Ácidos Borónicos/uso terapéutico , Línea Celular Tumoral , Portadores de Fármacos/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/uso terapéutico , Humanos , Nanotubos/química , Neoplasias/tratamiento farmacológico
12.
J Mater Chem B ; 9(44): 9142-9152, 2021 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-34693960

RESUMEN

Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In this study, a synergistic phototherapy and hypoxia-activated chemotherapy nanoplatform based on natural melanin nanoparticles (MPs) loaded with the bioreduction prodrug tirapazamine (TPZ) and decorated with hyaluronic acid (HA) was developed. A self-reporting aggregation-induced emission (AIE)-active photosensitizer (PS) (BATTMN) was linked to the prepared nanoparticles by boronate ester bonds. The MPs and BATTMN-HA played roles as quenchers for PS and cancer targeting/photodynamic moieties, respectively. As a pH sensitive bond, the borate ester bonds between HA and BATTMN are hydrolysed in the acidic cancer environment, thereby separating BATTMN from the nanoparticles and leading to the induction of fluorescence for imaging-guided synergistic phototherapy/hypoxia-activated chemotherapy under dual irradiation. TPZ can be released upon activation by pH, near-infrared (NIR) and hyaluronidase (Hyal). Particularly, the hypoxia-dependent cytotoxicity of TPZ was amplified by oxygen consumption in the tumor intracellular environment induced by the AIE-active PS in photodynamic therapy (PDT). The nanoparticles developed in our research showed favorable photothermal conversion efficiency (η = 37%), desired cytocompatibility, and excellent synergistic therapeutic efficacy. The proposed nanoplatform not only extends the application scope of melanin materials with AIE-active PSs, but also offers useful insights into developing multistimulus as well as multimodal synergistic tumor treatment.


Asunto(s)
Antineoplásicos/uso terapéutico , Portadores de Fármacos/química , Melaninas/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/química , Ácidos Borónicos/química , Ácidos Borónicos/efectos de la radiación , Ácidos Borónicos/uso terapéutico , Terapia Combinada , Quimioterapia , Femenino , Humanos , Células MCF-7 , Melaninas/química , Melaninas/efectos de la radiación , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanopartículas/efectos de la radiación , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Terapia Fototérmica , Profármacos/química , Profármacos/uso terapéutico , Tirapazamina/química , Tirapazamina/uso terapéutico , Hipoxia Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto
13.
J Control Release ; 330: 1168-1177, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33212120

RESUMEN

Inspired by our previous study, we report a simple yet effective platform for therapeutic antibody delivery. A polymeric phenylboronic acid (pPBA)-antibody nanocomplex was simply formulated by mixing pPBA and antibody, derived by the formation of a pH-responsive phenylboronic ester between the PBA group on pPBA and diol on the inherent glycosylation site of the antibody. We focused on the basic prerequisites for a successful delivery, protection from degradation during the circulation, and release at the target lesion. To evaluate the antibody delivery system, anti-PD-L1, one of the most common antibody therapeutics in immuno-oncology, and mouse colon cancer model with an MC-38 cell line were used. Several in-vitro assays reveal the outstanding protective effect of the nanocomplexes as well as the pH-responsive release of antibodies. Moreover, the anti-PD-L1 nanocomplex exhibited an enhanced circulation as well as a better accumulation in tumor lesions after administration in vivo, which led to a significant antitumor effect in comparison to that of a free antibody. Our nanocomplex platform is a promising antibody delivery system for application in conventional antibody-mediated therapies.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Animales , Ácidos Borónicos/uso terapéutico , Línea Celular Tumoral , Inmunoterapia , Ratones , Neoplasias/tratamiento farmacológico
14.
ACS Appl Mater Interfaces ; 13(8): 9390-9401, 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33155813

RESUMEN

In the present study, we report a rationally designed polymer/aptamer-integrated gold (Au) nanoconstruct capable of scavenging reactive oxygen species (ROS) and capturing tumor necrosis factor alpha (TNF-α) and investigate its potential as an anti-inflammatory agent for the treatment of peritonitis. By taking advantage of specific interactions between ATP and both ATP aptamer and polymeric phenylboronic acid (pPBA), we construct a unique polymer-coated Au nanoconstruct equipped with TNF-α aptamer and ATP aptamer. The formed phenylboronic ester and TNF-α aptamer in the nanoconstruct is capable of scavenging ROS and capturing of TNF-α, respectively. Thus, this combined characteristics enable the nanoconstruct an additive anti-inflammatory effect. Furthermore, we demonstrate the high anti-inflammatory effect of the nanoconstruct in vitro and in vivo using the peritonitis model by monitoring ROS and pro-inflammatory cytokine levels.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Aptámeros de Nucleótidos/uso terapéutico , Nanopartículas del Metal/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adenosina Trifosfato/química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Aptámeros de Nucleótidos/química , Ácidos Borónicos/química , Ácidos Borónicos/uso terapéutico , Femenino , Oro/química , Nanopartículas del Metal/química , Ratones , Ratones Endogámicos BALB C , Polímeros/química , Polímeros/uso terapéutico , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/química
17.
J Med Chem ; 63(14): 7491-7507, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32150407

RESUMEN

Despite major advances in the ß-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a ß-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.


Asunto(s)
Ácidos Borínicos/farmacología , Ácidos Borónicos/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores de beta-Lactamasas/farmacología , Animales , Bacterias/efectos de los fármacos , Ácidos Borínicos/química , Ácidos Borínicos/farmacocinética , Ácidos Borínicos/uso terapéutico , Ácidos Borónicos/química , Ácidos Borónicos/farmacocinética , Ácidos Borónicos/uso terapéutico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/uso terapéutico , Descubrimiento de Drogas , Infecciones por Klebsiella/tratamiento farmacológico , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacocinética , Inhibidores de beta-Lactamasas/uso terapéutico
18.
Artículo en Inglés | MEDLINE | ID: mdl-32094128

RESUMEN

The comparative efficacy of ceftazidime-avibactam and meropenem-vaborbactam for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections remains unknown. This was a multicenter, retrospective cohort study of adults with CRE infections who received ceftazidime-avibactam or meropenem-vaborbactam for ≥72 hours from February 2015 to October 2018. Patients with a localized urinary tract infection and repeat study drug exposures after the first episode were excluded. The primary endpoint was clinical success compared between treatment groups. Secondary endpoints included 30- and 90-day mortality, adverse events (AE), 90-day CRE infection recurrence, and development of resistance in patients with recurrent infection. A post hoc subgroup analysis was completed comparing patients who received ceftazidime-avibactam monotherapy, ceftazidime-avibactam combination therapy, and meropenem-vaborbactam monotherapy. A total of 131 patients were included (ceftazidime-avibactam, n = 105; meropenem-vaborbactam, n = 26), 40% of whom had bacteremia. No significant difference in clinical success was observed between groups (62% versus 69%; P = 0.49). Patients in the ceftazidime-avibactam arm received combination therapy more often than patients in the meropenem-vaborbactam arm (61% versus 15%; P < 0.01). No difference in 30- and 90-day mortality resulted, and rates of AE were similar between groups. In patients with recurrent infection, development of resistance occurred in three patients that received ceftazidime-avibactam monotherapy and in no patients in the meropenem-vaborbactam arm. Clinical success was similar between patients receiving ceftazidime-avibactam and meropenem-vaborbactam for treatment of CRE infections, despite ceftazidime-avibactam being used more often as a combination therapy. Development of resistance was more common with ceftazidime-avibactam monotherapy.


Asunto(s)
Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Ácidos Borónicos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Carbapenémicos , Ceftazidima/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Meropenem/uso terapéutico , Anciano , Estudios de Cohortes , Combinación de Medicamentos , Infecciones por Enterobacteriaceae/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Inhibidores de beta-Lactamasas/farmacología
19.
J Med Chem ; 63(6): 3104-3119, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-32031798

RESUMEN

Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.


Asunto(s)
Antibacterianos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Endopeptidasa Clp/antagonistas & inhibidores , Peptidomiméticos/uso terapéutico , Inhibidores de Serina Proteinasa/uso terapéutico , Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico , Animales , Antibacterianos/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Compuestos de Boro/farmacología , Ácidos Borónicos/metabolismo , Ácidos Borónicos/farmacología , Endopeptidasa Clp/metabolismo , Femenino , Glicina/análogos & derivados , Glicina/farmacología , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/enzimología , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Estructura Molecular , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacología , Unión Proteica , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Piel/patología , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Virulencia/efectos de los fármacos
20.
Orthop Nurs ; 39(1): 53-58, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31977743

RESUMEN

In recent years, government-backed policies have promoted the development of new antimicrobials to combat increases in antibiotic-resistant organisms. This article summarizes the 10 new antibacterial agents to be approved in the last 5 years.


Asunto(s)
Antibacterianos/uso terapéutico , Aprobación de Drogas , Compuestos de Azabiciclo/uso terapéutico , Ácidos Borónicos/uso terapéutico , Ceftazidima/uso terapéutico , Cefalosporinas/uso terapéutico , Cilastatina/uso terapéutico , Combinación de Medicamentos , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Humanos , Imipenem/uso terapéutico , Meropenem/uso terapéutico , Tazobactam/uso terapéutico
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